Synthesis and evaluation of pyrazolo[5,1-b]quinazoline-2-carboxylate, and its thiazole derivatives as potential antiproliferative agents and Pim-1 kinase inhibitors

Abstract

The multi-component reactions of compounds 2a–c with any of the aromatic aldehydes 3a–c and cyclohexane-1,4-dione gave the 2-hydroxy-5,6,8,9-tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives 5a–i, respectively. In addition compounds 5a–i reacted with elemental sulfur and phenylisothiocyanate to give the 8-hydroxy-3-phenyl-4,5,7,11-tetrahydropyrazolo[5,1-b]thiazolo[5,4-f]quinazoline-2(3H)-thione derivatives 7a–i. Compounds 5a–i were reacted with cyanoacetylhydrazine to give the 2-cyano-N′-(2-hydroxy-5,6-dihydropyrazolo[5,1-b]quinazolin-7(3H,8H,9H)-ylidene)acetohydrazide derivatives 9a–i. The reaction compounds 9a–i with elemental sulfur and phenylisothiocyanate and with thioglycollic acid gave the thiazole derivatives 11a–i and 13a–i, respectively. In the present work a series of novel quinazoline and their fused derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, prostate cancer cell lines and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The most promising compounds 5b, 5h, 5i, 7h, 9h, 9i, 11b, 11c, 11e, 13h, and 13i were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5h, 5i, 11e, and 13i were selected to examine their Pim-1 kinase inhibition activity where compounds 5i and 11e showed high activities. All target compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line.